Chlordiazepoxide Capsules Bp 10mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Chlordiazepoxide capsules BP 10 mg.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Chlordiazepoxide HCL BP 10.00 mg per capsule
3 PHARMACEUTICAL FORM
The product is presented in the form of size 4, dark green opaque/chocolate brown opaque capsules printed with CDZ 10 and company logo.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
a. Relief of anxiety: Benzodiazepines are indicated for the short-term relief (24 weeks) only of anxiety that is severe, disabling or subjecting the individual to unacceptable distress, occurring alone or in association with insomnia or short-term psychosomatic, organic or psychotic illness.
The use of benzodiazepines to treat short-term 'mild' anxiety is considered to be inappropriate and unsuitable.
b. Insomnia: Benzodiazepines should be used to treat insomnia only when it is severe, disabling, or subjecting the individual to extreme distress,
c. Symptomatic relief of acute alcohol withdrawal.
d. Control of muscle spasm.
4.2 Posology and method of administration
Posology:
Anxiety states:
Usual dose 10mg, 2-3 times a day and up to 30 mg daily in divided doses. For severe symptoms 20mg, 2-4 times a day. Maximum dose up to 100 mg daily in divided doses. Adjusted on an individual basis.
Generally, duration of treatment should not be more than 4 weeks, including a tapering-off process.
Insomnia associated with anxiety:
10 to 30 mg before retiring. Generally, duration of treatment varies from a few days to two weeks, with a maximum including a tapering-off process of four weeks.
Symptomatic relief of acute alcohol withdrawal:
25 to 100 mg and repeated if necessary in 2 to 4 hours.
Muscle spasm of varied aetiology:
10 to 30 mg daily in divided doses.
Paediatric patients
Chlordiazepoxide is not for paediatric use.
Special patient groups
Elderly or debilitated patients, patients with organic brain damage, respiratory impairment and/or hepatic or renal dysfunction should normally not exceed half of the doses normally recommended.
The lowest dose which can control symptoms should be used. The dosage and duration of treatment should be determined on an individual basis dependent by the patient’s response and severity of the disorder. Given that chlordiazepoxide is a long-acting benzodiazepine, the patient should be monitored regularly at the start of the treatment to decrease, if necessary, the dose or frequency of administration to prevent overdose due to accumulation.
Treatment should be as short as possible. The patient should be reassessed regularly and the need for continued treatment should be evaluated, especially in case the patient is symptom free.
Treatment should always be tapered off gradually. Patients who have taken benzodiazepines for a prolonged time may require a longer period during which doses are reduced. Specialist help may be appropriate.
Method of administration: Chlordiazepoxide capsules are for oral administration and must be taken with water and not be chewed.
4.3 Contraindications
Known sensitivity to benzodiazepines or to any of the excipients listed in section 6.1, severe pulmonary insufficiency, respiratory depression, phobic or obsessional states, chronic psychosis. Myasthenia gravis, sleep apnoea syndrome and severe hepatic insufficiency.
4.4 Special warnings and precautions for use
Tolerance
Some loss of efficacy to the hypnotic effects of benzodiazepines may develop after repeated use for a few weeks.
Dependence and withdrawal
The dependent potential of the benzodiazepines is low, particularly when limited to short-term use. Risk for physical and psychological dependence increases when high doses are used, especially when given over long periods. This is particularly so in patients with a history of alcoholism or drug abuse or in patients with marked personality disorders. Regular monitoring in such patients is essential. Routine repeat prescriptions should be avoided and treatment should be withdrawn gradually.
Symptoms such as headaches, muscle pain, extreme anxiety, restlessness, confusion, depression, nervousness, rebound insomnia, irritability, sweating and diarrhoea have been reported following abrupt cessation of treatment in patients receiving even normal therapeutic doses for short periods of time. In severe cases, the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations, psychotic manifestations or epileptic seizures.
Rebound insomnia and anxiety:
This is a transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.
Duration of Treatment
The duration of treatment should be as short as possible (see posology) depending on the indication, but should not exceed 4 weeks, including tapering-off process. Routine repeat prescriptions should be avoided.
It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage will be progressively decreased. Moreover, it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur while the medicinal product is being discontinued.
When benzodiazepines with a long duration of action are being used, it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.
Amnesia
Amnesia may occur. Benzodiazepines may induce anterograde amnesia. The condition occurs most often several hours after ingesting the product and therefore, to reduce the risk, patients should ensure that they will be able to have an uninterrupted sleep of 7-8 hours (see also Undesirable Effects).
Psychiatric and paradoxical reactions
Rare behavioural effects including restlessness, agitation, irritability, aggressiveness, excitement, confusion, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. Should these effects occur, use of the medicinal product should be discontinued. They are most likely to occur in children and the elderly.
Specific patient groups
Elderly patients should be given a reduced dose (see section 4.2). A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression. Benzodiazepines are contraindicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy and reduced doses should be given to patients with renal or hepatic disease.
Benzodiazepines are not recommended for the primary treatment of psychotic illness.
Chlordiazepoxide should not be used alone to treat depression or anxiety associated with depression, since it may uncover depression with suicidal tendencies. Extreme caution should be used in prescribing benzodiazepines to patients with personality disorders. Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.
In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.
Due to the myorelaxant effect there is a risk of falls and consequently fractures in the elderly.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
If chlordiazepoxide is combined with centrally-acting drugs such as neuroleptics, tranquillisers, antidepressants, hypnotics, analgesics, anaesthetics, and sedative antihistamines the central depressive effects are likely to be intensified. In the case of narcotic analgesics, enhancement of the euphoria may also occur leading to an increase in psychic dependence. The elderly require special supervision.
Concomitant intake with alcohol should be avoided. The sedative effect may be enhanced when the product is used in combination with alcohol. This adversely affects the ability to drive or use machinery.
When chlordiazepoxide is used in conjunction with antiepileptic drugs, side effects and toxicity may be more evident, particularly with hydantoins or barbiturates or combinations including them. Therefore extra caution is required in adjusting dosage in the initial stages of treatment.
Known inhibitors of hepatic enzymes e.g. cimetidine, omeprazole and disulfiram have been shown to reduce the clearance of benzodiazepines and may potentiate their action. The same applies to the use of contraceptive agents. Known inducers of hepatic enzymes, e.g. rifampicin, may increase the clearance of benzodiazepines.
In patients receiving long-term treatment with other medicines (such as centrally acting antihypertensive agents, beta receptor blockers, anticoagulant agents and cardiac glycosides), nature and extent of interactions cannot safely be foreseen.
Benzodiazepines possibly antagonise the effect of levodopa.
Sedative effects are possibly increased when benzodiazepines are given with moxonidine.
Benzodiazepines enhance effects of sodium oxybate. Concomitant use should be avoided.
Effects of benzodiazepines are possibly reduced by theophylline.
4.6 Fertility, pregnancy and lactation
Pregnancy:
There is no evidence as to drug safety in human pregnancy, nor is there evidence from animal work that it is free from hazard. Do not use during pregnancy, especially during the first and last trimesters, unless there are compelling reasons.
If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance of the product if she intends to become or suspects she is pregnant
The administration of high doses or prolonged administration of low doses of benzodiazepines in the last trimester of pregnancy has been reported to produce irregularities in the foetal heart rate, and hypotonia, poor sucking and hypothermia in the neonate.
Moreover, infants born to mothers who took benzodiazepines chronically during the later stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.
Breast feeding:
Chlorodiazepoxide may appear in breast milk. If possible the use of chlordiazepoxide should be avoided during breast feeding.
4.7 Effects on ability to drive and use machines
Patients should be advised that, like all medicaments of this type, chlordiazepoxide may modify patients' performance at skilled tasks. Sedation, amnesia, impaired concentration and impaired muscle function may adversely affect the ability to drive or use machinery. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased. Patients should further be advised that alcohol may intensify any impairment, and should, therefore, be avoided during treatment.
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
• The medicine is likely to affect your ability to drive
• Do not drive until you know how the medicine affects you
• It is an offence to drive while under the influence of this medicine
• However, you would not be committing an offence (called “statutory defence”) if:
- The medicine has been prescribed to treat a medical or dental problem and
- You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
- It was not affecting your ability to drive safely.
4.8 Undesirable effects
Common adverse effects include drowsiness, sedation, dizziness, unsteadiness and ataxia; these are dose-related and may persist into the following day even after a single dose. However, these phenomena occur predominantly at the start of therapy and usually disappear with repeated administration. The elderly are particularly sensitive to the effects of centrally-depressant drugs and may experience confusion, especially in the presence of organic brain changes; and the dosage of chlordiazepoxide should not exceed one-half that recommended for other adults.
Evaluation of undesirable effects is based on the following frequency information: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); not known (frequency cannot be estimated from available data).
Blood and lymphatic system disorders:
Rare: Bone marrow depression (e.g. thrombocytopenia, leukopenia, agranulocytosis, pancytopenia).
Immune system disorders:
Very rare: Anaphylactic reaction, angioedema. Frequency not known: Hypersensitivity. Psychiatric disorders:
Frequency not known: Amnesia, hallucinations, dependence, depression, restlessness, agitation, irritability, depressed level of consciousness, aggression, delusion, nightmares, psychotic disorder, abnormal behaviour, emotional disturbances, paradoxical drug reaction (e.g. anxiety, sleep disorders, insomnia, suicide attempt, suicidal ideation).
Nervous system disorders:
Common: sedation, dizziness, unsteadiness, somnolence, ataxia, balance disorder, confusional states.
Rare: Headache, vertigo.
Frequency not known: Dysarthria, gait disturbance, extrapyrimidal disorder (e.g. tremor, dyskinesia).
Eye disorders:
Rare: Visual impairment including diplopia. Vascular disorders:
Rare: Hypotension.
Respiratory, thoracic and mediastinal disorders: Frequency not known: Respiratory depression.
Gastrointestinal disorders:
Rare: Gastrointestinal upsets.
Hepatobiliary disorders:
Frequency not known: Jaundice, blood bilirubin increased, transaminases increased, blood alkaline phosphatase increased.
Skin and subcutaneous tissue disorders:
Rare: Skin reaction (e.g. rash).
Musculoskeletal and connective tissue disorders:
Due to the myorelaxant effect there is a risk of falls and consequently fractures in the elderly.
Frequency not known: Muscle weakness.
Renal and urinary disorders:
Rare: Urinary retention, incontinence.
Reproductive system and breast disorders:
Rare: Libido disorders, erectile dysfunction, menstrual disorder.
General disorders and administration site conditions:
Common: Fatigue.
Frequency not known: Changes in salivation.
Amnesia
Anterograde amnesia may occur at the therapeutic doses, with increasing risk at higher doses. This may be associated with inappropriate behaviour (see section 4.4).
Depression
Pre-existing depression may be unmasked by benzodiazepines.
Psychiatric and paradoxical reactions
Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepine-like agents. They may be quite severe with this product. They are more likely to occur in children and the elderly.
Dependence
Use (even therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in the withdrawal or rebound phenomena. Psychological dependence may occur. Abuse of benzodiazepines has been reported.
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
When taken alone in overdosage, chlordiazepoxide presents few problems in management. When taken with centrally-acting drugs, especially alcohol, the effects of overdose are likely to be more severe and in the absence of supportive measures may prove fatal.
Symptoms:
Overdose of benzodiazepines is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, dysarthria, mental confusion and lethargy, in more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death.
Management:
In the management of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken.
Treatment is symptomatic.
The benefit of gastric decontamination is uncertain. Consider activated charcoal (charcoal dose: 50g for an adult, 1g/kg for a child) in adults or children who have taken more than a potentially toxic amount within 1 hour, provided the airway can be protected.
The value of dialysis has not been determined. Flumazenil, a benzodiazepine antagonist, is available but should rarely be required. It may be required in children who are naive to benzodiazepines or patients with COPD as an alternative to ventilation. Flumazenil has a short half-life (about an hour) and in this situation an infusion may therefore be required. Flumazenil should not normally be used in patients with a history of seizures, head injury, chronic benzodiazepine use, co-ingestion of a benzodiazepine and tricyclic antidepressant or other proconvulsant.
If excitation occurs, barbiturates should not be used.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Chlorodiazepoxide is a benxodiazepine tranquilliser with anticonvulsant, sedative, muscle relaxant and amnesiac properties.
Chlordiazepoxide acts as depressant of the central nervous system producing all levels of CNS depression, from mild sedation to hypnosis, to coma depending on the dose. The precise sites and mechanisms of action have not been fully established but various mechanisms have been proposed. It is believed that chlordiazepoxide enhances or facilitates the inhibitory neurotransmitter action of gama-aminobutyric acid (GABA) which mediates both pre- and post synaptic inhibition in all regions of the CNS following interaction between Chlordiazepoxide and a specific neuronal membrane receptor. Antianxiety action of chlordiazepoxide is believed to result from stimulation of GABA receptors in the ascending reticular activating system. Since GABA in inhibitory receptor stimulation increases inhibition and blocks both cortical and limbic arousal following stimulation of the brainstem reticular formation.
The exact mechanism of actions of chlordiazepoxide are not fully established but skeletal muscle relaxation primarily occurs by inhibiting spinal polysynaptic afferent pathways but it may also inhibit monosynaptic afferent pathways. The adult dose for various degree of anxiety range from 6-30 mg daily in divided doses.
5.2 Pharmacokinetic properties
Chlordiazepoxide is readily absorbed from the gastrointestinal tract with peak blood levels being achieved one or two hours after administration. Rate of absorption is age-related and tends to be delayed in the elderly. After absorption it is highly bound to plasma proteins. The drug has a half-life of 630 hours. Steady-state is usually reached within three days. Chlordiazepoxide is extensively metabolised in the liver by hepatic microsomal enzymes and exhibit capacity limited protein binding sensitive hepatic clearance.
Pharmacologically active metabolites of chlordiazepoxide include desmethylchlordiazepoxide demoxepam, desmethlydiazepam and oxazepam.
The active metabolite desmethylchlordiazepoxide has an accumulation halflife of 10-18 hours and that of demoxepam has been recorded as 21-78 hours. Steady-state level of these active metabolites are reached after 10-15 days; with metabolite concentrations which are similar to those of the parent drug.
Chlordiazepoxide is distributed in the CSF corresponding to the free fraction of chlordiazepoxide. It enters the brain following a rapid distribution phase in grey matter with its high blood flow, followed by a longer accumulation phase of chlordiazepoxide and its metabolites in the white matter. The accumulation is more marked following repeated dosage. Chlordiazepoxide has a high affinity for lipids.
Chlordiazepoxide is excreted mainly in the urine mainly in the form of its metabolites; only a small percent of this is in free form most being excreted as conjugates with glucuronide or sulphate. There is no biliary excretion.
5.3 Preclinical safety data
Not applicable.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose BP
Magnesium stearate BP Capsule shell components Body
Red iron oxide (E172) HSE Black iron oxide (E172) HSE Titanium dioxide (E171) HSE Gelatin USP
Cap
Quinolene Yellow (E104) HSE Indigotine (E132) HSE Titanium Dioxide (E171) HSE Gelatin USP
6.2 Incompatibilities
None.
6.3 Shelf life
5 years when stored as recommended.
2 years - Blister packs.
6.4 Special precautions for storage
Protect from heat, light and moisture. Keep out of the reach of children.
6.5 Nature and contents of container
The product is packed in:
1 Opaque plastic containers composed of polypropylene tubes and polyethylene made tamper-evident closures in pack sizes of 28, 30, 42, 50, 56, 60, 84, 90, 100, 112, 250, 500 and 1,000 capsules.
2 Opaque plastic containers composed of either high density polypropylene or high density polyethylene with a tamper-evident or child-resistant tamper-evident closure composed of high density polyethylene in pack sizes of 28, 30, 42, 50, 56, 60, 84, 90, 100, 112, 250, 500 and 1,000 capsules.
3. HDPE container with PP lid & induction seal liner. Pack size of 100 capsules.
4. The product is packed in blister packs of aluminium / opaque PVC in
7
8
9
10
pack sizes of 28, 30, 42, 56, 60, 84, 90 and 112 capsules.
MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited
Unit 3&4 Quidhampton Business Units
Polhampton Lane
Overton
Hampshire
RG25 3ED
United Kingdom
09/09/2015